Regulation of human organic anion transporter 3 by peptide hormone bradykinin.

نویسندگان

  • Shanshan Li
  • Peng Duan
  • Guofeng You
چکیده

Human organic anion transporter (hOAT) 3 belongs to a family of organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. In the current study, we examined the regulation of hOAT3 by peptide hormone bradykinin (BK) in COS-7 cells. BK (<or=500 nM) induced a concentration- and time-dependent stimulation of hOAT3 activity, kinetically revealed as an increased V(max). Such an increase in V(max) resulted from an increased cell surface expression without a change in total cell expression of the transporter. BK-induced stimulation of hOAT3 activity could be prevented by treating hOAT3-expressing cells with staurosporine, a general inhibitor for protein kinase C (PKC). To obtain further information on which PKC isoform mediates BK regulation of hOAT3 activity, cellular distribution of various PKC isoforms was examined in cells treated with BK. We showed that BK treatment resulted in a significant translocation of PKCdelta, PKCepsilon, and PKCzeta from cytosol to membrane. We further showed that BK treatment enhanced association of hOAT3 with PKCdelta, PKCepsilon, and PKCzeta and that isoform-specific inhibitor for PKCdelta, PKCepsilon, and PKCzeta reversed BK effect on hOAT3 activity. We therefore concluded that BK stimulated hOAT3 activity through activation of PKCdelta, PKCepsilon, and PKCzeta, which then led to the redistribution of hOAT3 from the intracellular compartments to the cell surface and to the up-regulation of hOAT3 activity.

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عنوان ژورنال:
  • The Journal of pharmacology and experimental therapeutics

دوره 333 3  شماره 

صفحات  -

تاریخ انتشار 2010